Viperin binds STING and enhances the type-I interferon response following dsDNA detection

Viperin is an interferon-inducible protein that is pivotal for eliciting an effective immune response against an array of diverse viral pathogens. Here we describe a mechanism of viperin9s broad antiviral activity by demonstrating the protein9s ability to synergistically enhance the innate immune dsDNA signalling pathway to limit viral infection. Viperin co-localised with the key signalling molecules of the innate immune dsDNA sensing pathway, STING and TBK1; binding directly to STING and inducing enhanced K63-linked polyubiquitination of TBK1. Subsequent analysis identified viperin9s necessity to bind the cytosolic iron-sulphur assembly component 2A, to prolong its enhancement of the type-I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signalling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signalling pathway; which results in an enhanced antiviral state. We also provide evidence for viperin9s radical SAM enzymatic activity as an intrinsic self-limiting function of its immunomodulatory functions. This data further defines viperin9s role as a positive regulator of innate immune signalling, offering a mechanism of viperin9s broad antiviral capacity.